Old but New: Group IIA Phospholipase A₂ as a Modulator of Gut Microbiota

Among the phospholipase A₂ (PLA₂) superfamily, the secreted PLA₂ (sPLA₂) family contains 11 mammalian isoforms that exhibit unique tissue or cellular distributions and enzymatic properties. Current studies using sPLA₂-deficient or -overexpressed mouse strains, along with mass spectrometric lipidomics to determine sPLA₂-driven lipid pathways, have revealed the diverse pathophysiological roles of sPLA₂s in various biological events. In general, individual sPLA₂s exert their specific functions within tissue microenvironments, where they are intrinsically expressed through hydrolysis of extracellular phospholipids. Recent studies have uncovered a new aspect of group IIA sPLA₂ (sPLA₂-IIA), a prototypic sPLA₂ with the oldest research history among the mammalian PLA₂s, as a modulator of the gut microbiota. In the intestine, Paneth cell-derived sPLA₂-IIA acts as an antimicrobial protein to shape the gut microbiota, thereby secondarily affecting inflammation, allergy, and cancer in proximal and distal tissues. Knockout of intestinal sPLA₂-IIA in BALB/c mice leads to alterations in skin cancer, psoriasis, and anaphylaxis, while overexpression of sPLA₂-IIA in Pla2g2a-null C57BL/6 mice induces systemic inflammation and exacerbates arthritis. These phenotypes are associated with notable changes in gut microbiota and fecal metabolites, are variable in different animal facilities, and are abrogated after antibiotic treatment, co-housing, or fecal transfer. These studies open a new mechanistic action of this old sPLA₂ and add the sPLA₂ family to the growing list of endogenous factors capable of affecting the microbe-host interaction and thereby systemic homeostasis and diseases.